9β,10α-Cholesta-5,7-diene-3β,25-diol

ABSTRACT

A method for preparing 9β,10α-chloesta-5,7-diene-3β,25 diol and 25-hydroxyprevitamin D 3  by irradiation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of copending applicationSer. No. 551,698, filed Feb. 21, 1975 now U.S. Pat. No. 4,001,096.

BRIEF DESCRIPTION OF THE PRIOR ART

25-Hydroxycholecalciferol is a newly discovered metabolite of VitaminD₃. A number of methods are available for preparing25-hydroxycholecalciferol. Among these methods is the thermalrearrangement of the 25-hydroxy previtamin D₃ schematic figure below, to25-hydroxycholecalciferol, Campbell, Squires and Babcock, Steroids,13,467 (1969). ##STR1##

The previtamin can be prepared by the irradiation ofcholesta-5,7-diene-3β,25-diol, as stated in the previous reference.

BRIEF SUMMARY OF THE INVENTION

It has now been found that the novel compound9β,10α-cholesta-5,7-diene-3β,25-diol is prepared by the irradiation ofcholesta-5,7-diene-3β,25-diol. This new compound can be isolated incrystalline form from the reaction mixture. Thereafter, the 9β,10αcompound can be irradiated to form 25-hydroxy previtamin D₃. Therefore,the methods of this invention result in increased yields of25-hydroxycholecalciferol.

In accordance with this invention, a method for producing9β,10α-cholesta-5,7-diene-3β,25-diol is disclosed, which comprisesirradiating cholesta-5,7-diene-3β,25-diol. The crystalline product canbe recovered from the reaction mixture.

A further aspect of the invention is the method of producing the25-hydroxyprevitam D₃ which comprises irradiating9β,10α-cholesta-5,7-diene-3β-25-diol.

A still further aspect of the invention is the novel compound9β,10α-cholesta-5,7-diene-3β-25-diol, schematic FIG. II below:

DETAILED DESCRIPTION OF THE INVENTION

The irradiation of the cholesta-5,7-diene-3β,25-diol is carried out byconventional, art recognized methods as used in the cited reference. Itis preferred to use radiation of wavelength greater than about 270-280-mμ to effectuate the transformation. The reaction product 25-hydroxyprevitamin D₃ is in photochemical equilibrium with the starting materialand is also in equilibrium with the 9β,10α-cholesta-5,7-diene-3β-25-dioland 25-hydroxy tachysterol₃, a further reaction product. The use ofradiation of wavelength greater than 270-280mμ reduces the quantity of25-hydroxy tachysterol₃ side product and increases the quantity of9β,10α-cholesta-5,7-diene-3β,25-diol produced.

A convenient source of radiation is a medium pressure mercury lamp. Inorder to achieve radiation of the preferred wavelength, this radiationcan be passed through Corex® glass of a thickness of 2 mm. Corex® glassis obtained from Corning Company.

The time of radiation is directly related to the lamp intensity. Thereaction course can be followed by analysis of the reaction mixture bygas-liquid chromatographic means. When an appropriate concentrationlevel of the desired compound is reached, the reaction is terminated.The weaker the intensity of radiation, the longer the reaction time.

The temperature of the irradiated solution is not unduly significant.Temperatures of from about -10° to about 20° C. can be readily employed.It is preferable to maintain a range of from about 0° to about 10° C. tolimit the production of the vitamin.

The cholesta-5,7-diene-3β,25-diol is irradiated in solution. Any organicsolvent which does not interfere detrimentally with the course ofreaction can be employed. Typical of such solvents are dialkylethers oftwo to eight carbon atoms, inclusive, and cyclic ethers of four to eightcarbon atoms, inclusive. Illustrative examples of these solvents arediethylether, dibutylether, ethylpropylether, tetrahydrofuran,1,4-dioxane and like molecules.

The irradiation of the solution can be carried out as disclosed above,however, it is preferred to have the solution essentially oxygen free.It is well known that free oxygen contributes to the increase ofundesirable side reactions. Oxygen can be removed from the solution bystandard methods such as a nitrogen purge.

The conversion of 9β,10α-cholesta-5,7-diene-3β,25-diol to the25-hydroxyprevitamin D₃ by irradiation is carried out in the same manneras the irradiation of cholesta-5,7-diene-3β,25-diol. Radiation above270-280 mμ is preferred. The irradiation is carried out in a solutionwhich is preferably essentially free of oxygen. The same type ofsolvents disclosed previously can also be used for this reaction. Thereaction temperature is maintained at the same range as the previousirradiation.

The following specific examples serve to illustrate the scope of theinvention. They are not intended to narrow the invention.

EXAMPLE 1 9β,10α-cholesta-5,7-diene-3β,25-diol

25.0 g. of cholesta-5,7-diene-3β,25-diol dissolved in 4.7 l. of dryoxygen-free tetrahydrofuran is irradiated for nineteen hours with amedium pressure mercury lamp, the light of which is filtered throughCorex® glass of 2 mm. thickness. The temperature is kept below 15° C.throughout this period. The solution is then evaporated to dryness at atemperature of less than 35° C. The residue is slurried with 75 ml.ethyl acetate and 130 ml. of Skellysolve B and cooled to 0° C. The solidwhich is starting material is filtered and the filtrate is nowevaporated. The residual oil is dissolved in 200 ml. benzene and stirredat 70° C. for sixteen hours under a blanket of nitrogen. The solution isthen evaporated and the residue dissolved in aqueous acetone from which25-hydroxycholecalciferol hydrate crystallizes. This is filtered off andthe filtrate evaporated to dryness. The residue is chromatographed onFlorisil and eluted with a mixture of ethyl acetate and Skellysolve B.There is obtained a first fraction from which more25-hydroxycholecalciferol hydrate is obtained and then a fraction fromwhich 9β,10α-cholesta-5,7-diene-3β,25-diol is obtained as white crystalsfrom acetonitrile, M.P. 122°-125° C.

NMR (CDCl₃): δ0.63s (3H); 0.75s (3H); 1.20s (6H); 4.10m (1H); 5.57 ABJ=ca 6H_(z) (2H); α_(D) (CHCl₃): +185°

EXAMPLE 2 Preparation of 25-hydroxyprevitamin D₃

9β,10α-cholesta-5,7-diene-3β,25-diol (5.0 g.) in 1 l. dry oxygen-freetetrahydrofuran, is irradiated in a like fashion to that described inExample 1. Working up in an analogous fashion to Example 1, somecholesta-5,7-diene-3β,25-diol is initially isolated. After a thermaltreatment of the materials contained in the filtrate, similar to that ofExample 1, 25-hydroxycholecalciferol is isolated.

I claim:
 1. Crystalline 9β,10α-cholesta-5,7-diene-3β,25-diol. 